PROJECT SUMMARY The survival rate of colorectal cancer and breast cancer as measured by Mortality to incidence ratios (MIRs) is worse among American Indian and Alaskan Native (AI/AN) population as compared to the white population. AI/AN individuals are more likely to be diagnosed with late-stage disease and this leads to poor treatment outcomes and increased mortality. These disparities in cancer within the AI/AN population is compounded by resistance to existing therapies and a high relapse rates among patients. Thus, there is a need to develop novel therapies to cure treatment resistant breast cancer. This study aims to alleviate these disparities faced by the AI/AN population by testing out a new cellular therapeutic approach to treat cancer. NK cells are a key component of the innate immune system and play an important role in early immunity to cancer by killing a variety of tumors. Adoptive transfer of NK cells and NK cell lines is a significant mode of cellular therapy that is being tested in various clinical trials to treat cancers. Efforts are being made to enhance the cytotoxic effects of NK cells and NK cell lines by treating them ex-vivo with different modulating agents. In our recent study, we found that NK cells when treated with reovirus become activated and show an enhanced cytotoxicity against tumor cells. In this project, we will test the ability of reovirus to increase the cytotoxicity of a NK cell line, NK-92MI, against human colorectal cancer cell line-DLD-1. Subsequently, we will perform an adoptive transfer of the reovirus activated NK-92MI cells to treat mice bearing DLD-1 tumors. Results from this study will increase our understanding of NK cell mediated antitumor response and help us develop new strategies to enhance NK cell cytotoxic functions for cancer treatment. Successful completion of this study will provide us with a novel cellular anti-cancer therapy with a potential to be translated into the clinic.